COVID19_GWAS

Brian M. Schilder, Bioinformatician II
Raj Lab
Department of Neuroscience
Icahn School of Medicine at Mount Sinai
NYC, New York

knitr::opts_chunk$set(echo = T)

library(catalogueR)
library(dplyr) 
root <- getwd()
hpc_root <- "/sc/arion/projects/pd-omics/brian/COVID19_GWAS"

Objectives

• Use catalogueR to query all 110 datasets in the eQTL Catalogue for eQTLs that overlap with COVID-19 GWAS-nominated SNPs.
• Identify which tissues, cell-types, and genes may be most relevant for genetic COVID-19 susceptibility.

Import and prepare SNPs

DAT <- readxl::read_excel("data/GCST90000255and6_GRCh38_Plessthan1eMinus5_combined_pruned.xlsx") %>%
  dplyr::rename(SNP=`SNP ID`, 
                CHR=chromosome, 
                POS=base_pair_location,
                A1=effect_allele,
                A2=other_allele,
                Effect=beta,
                StdErr=standard_error,
                P=p_value) %>%
  dplyr::mutate(Locus=SNP)
 
createDT(DAT)

Since catalogueR expects a list of files with per-Locus summary stats, we’ll just save each SNP as its own “locus” file.

sumstats_paths <- lapply(1:nrow(DAT), function(i){
  ROW <- DAT[i,]
  # printer(ROW$SNP) 
  out <- file.path("data/sumstats",ROW$SNP,paste0(ROW$SNP,"_COVID19.tsv"))
  dir.create(dirname(out), showWarnings = F, recursive = T)
  data.table::fwrite(ROW, out, sep="\t")
  return(out) 
}) %>% unlist() 

Query eQTL Catalogue

Run on computing cluster

GWAS.QTL <- catalogueR::eQTL_Catalogue.query(sumstats_paths = sumstats_paths,
                                             # qtl_search = "CEDAR.monocyte_CD14",
                                             
                                             genome_build = "hg38",
                                             force_new_subset = T,
                                             progress_bar = F,
                                             merge_with_gwas = T,
                                             split_files = F,
                                             nThread = 4) 

Import results

GWAS.QTL <- data.table::fread(file.path(root,"catalogueR_queries/eQTL_Catalogue.tsv.gz"), nThread = 4)

Summarise

Annotate tissues using metadata

GWAS.QTL <- eQTL_Catalogue.annotate_tissues(dat = GWAS.QTL)  

Count the number of unique SNPs, eQTL genes, significant eGenes per tissue/cell-type.

Note: eQTL Catalogue only provides raw p-values, so you’ll need to infer your own signficance correction threshold. For simplicity, I use p < 5e-8 here.

GWAS.QTL <- dplyr::mutate(GWAS.QTL, FDR.QTL=stats::p.adjust(p = pvalue.QTL, method = "fdr"))
# p_thresh <- 5e-8
fdr_thresh <- 0.05


counts <- GWAS.QTL %>% 
  dplyr::group_by(System, Tissue_group, Tissue) %>% 
  dplyr::summarise(variants=dplyr::n_distinct(SNP),
                   eVariants=dplyr::n_distinct(SNP[FDR.QTL<fdr_thresh]),
                   genes=dplyr::n_distinct(gene.QTL),
                   eGenes=dplyr::n_distinct(gene.QTL[FDR.QTL<fdr_thresh]),
                   eGenes_names=paste(unique(gene.QTL[FDR.QTL<fdr_thresh]), collapse = ", "),
                   studies=dplyr::n_distinct(Study),
                   studies_names=paste(unique(Study), collapse = ", ")) %>%
  dplyr::arrange(desc(variants),desc(eVariants),
                 desc(genes), desc(eGenes))

## `summarise()` regrouping output by 'System', 'Tissue_group' (override with `.groups` argument)

createDT(counts)

Plot

library(ggplot2)

GWAS.QTL$Tissue <- factor(GWAS.QTL$Tissue, levels = unique(counts$Tissue), ordered = T)

gp <- ggplot(data = subset(GWAS.QTL, FDR.QTL< fdr_thresh), 
       aes(x= gene.QTL, y= Tissue, color=P, size= FDR.QTL)) +
  geom_point(alpha=1) + 
  scale_color_viridis_c(direction = -1) +    
  facet_grid(facets = System ~.,
             space = "free_y",
             scales = "free_y") +
  guides(size = guide_legend(reverse=T)) +
  labs(title = "Variant overlap: COVID-19 GWAS vs. eQTL Catalogue",
       subtitle = paste("QTL FDR <",fdr_thresh)) +
  theme_bw() +
  theme(axis.text.x = element_text(angle = 45, hjust = 1),
        strip.background = element_rect(fill="grey20"),
        strip.text = element_text(color="white"))
print(gp)

ggsave("plots/COVID19_GWAS.summary.png", gp, dpi=300)

## Saving 9 x 7.5 in image

Save annotated and FDR-corrected results

data.table::fwrite(GWAS.QTL, file.path(root,"catalogueR_queries/eQTL_Catalogue.annotated.tsv.gz"))